(Circulation. 1995;92:3387-3389.)
© 1995 American Heart Association, Inc.
Articles |
Localization of a Gene Responsible for Familial Dilated Cardiomyopathy to Chromosome 1q32
From the Baylor College of Medicine, Houston, Tex; Kaiser Permanente Hospital, Los Angeles, Calif (J.M.G.); University of Texas Houston Health Science Center (S.D.); and the University of Utah, Salt Lake City (J.L.A.).
Correspondence to Robert Roberts, MD, Don W. Chapman Professor of Medicine, Professor of Cell Biology, Baylor College of Medicine, 6550 Fannin, MS SM677, Houston, TX 77030. E-mail eyeager@bcm.tmc.edu or dweaver@bcm.tmc.edu.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Dilated cardiomyopathy, characterized by ventricular dilatation and decreased systolic contraction, is twofold to threefold more common as a cause of heart failure than hypertrophic cardiomyopathy and costs several billion dollars annually. The idiopathic form occurring early in life, with a 75% mortality in 5 years, is a common reason for transplantation. It is estimated that at least 20% of cases are familial.
Methods and Results A family of 46 members spanning four
generations underwent history and physical examinations,
echocardiographic analysis, and blood sampling
for genotyping. Diagnostic criteria, detected by
echocardiography, consisted of
ventricular dimension of 
2.7 cm/m2 with an
ejection fraction 
50% in the absence of other potential causes. DNA
from all members was analyzed by polymerase chain reaction for
amplification of short tandem-repeat polymorphic markers
located every 10 cM throughout the human genome. Assuming a penetrance
of 90%, linkage analysis was performed to map the responsible
chromosomal locus. Linkage analysis, after 412 markers were
analyzed, indicated the locus to be on chromosome 1q32, with a
peak multipoint logarithm of the odds score at D1S414 of 6.37.
Conclusions The locus identified in this study for familial dilated cardiomyopathy, 1q32, is rich in candidate genes, such as MEF-2, renin, and helix loop helix DNA binding protein MYF-4. Identification of the genetic defect could provide insight into the molecular basis for the cardiac dilatory response in both familial and acquired disorders.
Key Words: cardiomyopathy • molecular biology • heart failure • genetics
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Cardiac failure is the fastest-growing cardiovascular entity in the Western world, with more than 400 000 new cases per year in the United States1 at a cost for cardiac transplantation of $200 million and for all cardiac failure of more than $10 billion.1 The estimated prevalence2 of dilated cardiomyopathy (DCM) in the United States is 36.5 per 100 000, and it is the most common reason for cardiac transplantation. Heart failure due to DCM is a lethal disease, with a 5-year mortality of 75%, the only cure being cardiac transplantation.3 The causes of DCM are diverse, ranging from ischemia to infection. Certain familial neuromuscular diseases, such as myotonic dystrophy,4 Duchenne muscular dystrophy,5 and a recently identified cardiac conduction disorder6 are associated with DCM. An X-linked cardiomyopathy has been mapped to the Duchenne muscular dystrophy gene, and Barth's syndrome has been mapped to Xq28.5 7 8 Frequently, heart failure due to DCM is of unknown cause and is referred to as idiopathic. Although a recent study indicated that 20% of DCM is inherited, the precise incidence remains to be determined.2 No gene defect has yet been identified for this disease. Idiopathic DCM, a primary cardiac disease characterized by ventricular dilatation and impaired systolic contraction, is manifested clinically by either sudden death or pump failure. A large family residing in California and Utah (family 20-022) was identified with familial DCM (FDCM), and the locus was mapped to chromosome 1q32.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Clinical Evaluation
After informed consent was obtained within the guidelines of Baylor College of Medicine and The Methodist Hospital, the family members were clinically evaluated by detailed history and physical examination, including 12-lead ECG; M-mode, two-dimensional echocardiography; and Doppler ultrasonography. Blood samples were obtained from all affected and unaffected individuals for a total of 46 patients. The criteria for diagnosis of DCM were determined from echocardiographic analysis consisting of an ejection fraction of
50%, a
regional fractional shortening of <27% on M-mode analysis, or
both in the presence of a left ventricular internal
diastolic dimension of 2.7 cm/m2 of body
surface area.9 In addition, other diseases that may
simulate FDCM had to be excluded, namely, coronary artery
disease, myocarditis, hypertension, and isolated right
ventricular DCM. Individuals who satisfied the
echocardiographic criteria of ventricular
dilatation without the criteria of decreased ejection fraction or
regional fractional shortening, or vice versa, were classified as
indeterminate, as were individuals with a concomitant disease that
could simulate the phenotype. In the computerized
analysis, individuals classified as indeterminant were referred
to as having an unknown diagnosis.
Genotyping Studies
Transformed cell lines were established
from lymphocytes,
and DNA was extracted by the salting-out
procedure.10 11 Chromosomal markers located 
10 cM
apart
were selected on the basis of their polymorphic information content
and were chosen primarily from the Genethon or National Institutes of
Health–CEPH genetic maps and analyzed as previously
described.12
Linkage Analysis
Two-point linkage analysis was conducted on
a
personal computer using version 5.2 of the
LINKAGEprogram.13 Multipoint linkage analysis was
conducted on a VAX computer using FASTLINK.
Autosomal-dominant inheritance was assumed, and penetrance was set
at 90%. The allele frequencies for the disease and the normal
allele were assumed to be 0.0001 and 0.9999, respectively, and
allele frequencies for microsatellite markers were arbitrarily set
equal to 1/n.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Clinical Findings
The family consists of 59 members spanning four generations (Figure
). Analysis was performed on the 46
living members, of whom 10 are affected. Thirty-one individuals
were shown to be clinically normal as determined by
echocardiographic criteria (see "Methods"). In 5,
the criteria for FDCM were not met because of either concomitant
disease that could simulate the phenotype or findings that were
borderline for the criteria, and they were designated as phenotypically
indeterminant in the linkage analysis. Analysis of the
pedigree indicates a pattern of inheritance consistent with
autosomal dominance and high penetrance. Among the 10 living affected
individuals, the onset of symptoms generally occurred in the second
decade. However, echocardiographic manifestations of
the disease were present in at least 2 individuals before the age
of 10 years. Among the individuals who died, autopsy analysis
showed that 1 individual died of the disease at 2.5 years of age. Two
of the individuals who underwent DNA analysis received cardiac
transplants, making a pathological diagnosis of DCM possible. The ages
of the living affected individuals varied from 9 to >70 years, with 6
individuals asymptomatic.
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Linkage Analysis
We performed a random genome search on 46
individuals using
412 short tandem-repeat polymorphisms. Two-point and
multipoint linkage analyses were conducted assuming penetrance
to be 90%. Among the regions excluded were the locus for the DCM
associated with a cardiac conduction defect6 at 1p1-1q1
and the locus for DCM on 9q23.14 Seven markers gave
logarithm of the odds (LOD) scores >3 in the 1q32 region
(Table). A peak LOD score of 5.82 was obtained at the
marker D1S414, with 
=0% recombination. The peak multipoint LOD
score, also at D1S414, was 6.37, with a support interval of 20 cM.
Setting marker allele frequencies to those calculated from
unrelated individuals did not markedly alter LOD scores. LOD scores
were also robust for penetrance for the most closely linked markers and
did not drop below 3 when penetrance was varied from 60% to 98%.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Genetic linkage analysis indicates that the gene responsible for DCM in a large kindred is located on the long arm of chromosome 1 (1q32). A uniform, objective diagnostic criterion was strictly adhered to in defining the characteristic cardiac manifestations of this disease. Individuals who satisfied this criterion but had other diseases that simulate the phenotype were classified as indeterminate. The incidence of the familial form and the percentage of cases due to the 1q32 locus remain to be determined. Nevertheless, families with FDCM can now be screened rapidly for genetic linkage to those markers in the 1q32 region known to be linked to the disease. For those families in which the disease does not map to 1q32, exclusion of this locus will accelerate the mapping of other loci.
It is difficult to postulate a likely candidate for DCM; however, the sarcomeric proteins must be considered, as must growth factors and/or mediators of the growth response. In familial hypertrophic cardiomyopathy, the abnormality is associated with increased cardiac growth (hypertrophy), whereas in FDCM, there appears to be an inappropriate growth response, giving rise to a normal or thinned wall ventricle with a dilated chamber. However, whether FDCM is a peculiar growth response or represents impaired growth remains speculative. Likely candidate genes in the 1q32 region include MYF4, MEF2D, FMOD, REN, and PMCA4. Studies are now under way using the positional candidate gene approach to isolate and identify the responsible gene. In addition to providing further understanding of the molecular basis for FDCM, identification of the gene should also provide a means to screen for individuals who are at risk before the development of this disease, which is a necessary step in our ultimate goal of providing effective prevention and treatment.
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Acknowledgments |
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This work was supported in part by grants from the National Heart, Lung, and Blood Institute Specialized Centers of Research (P50-HL-42267-01), the National Institutes of Health Training Center in Molecular Cardiology (T32-HL-07706), and the American Heart Association Bugher Foundation Center for Molecular Biology (86-2216) and Robert Wood Johnson Minority Medical Award (23231). A portion of this work was performed in the Phoebe Willingham Muzzy Pediatric Molecular Cardiology Laboratory. We would like to acknowledge Dr Ronald Karlsberg and his colleagues and Dr Ronald M. Rosengard for their support in helping us screen the family members in Los Angeles. We greatly appreciate the secretarial assistance of Debora Weaver and Esther Yeager in the preparation of this manuscript and figures.
Received October 10, 1995; revision received October 25, 1995; accepted October 25, 1995.
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